Given the prevalence of thyroid disorders and the subtle signs and symptoms that may accompany subclinical disease, reliable laboratory testing for serum TSH and free thyroid hormones is important for both primary care physicians and endocrinologists. The laboratory community has recognized the need for standardization of thyroid function tests to achieve comparability of measurement results between methods. This applies in particular to tests for free T4 (FT4), which may be considered controversial in terms of clinical and analytical validity. However, variability is also observed with TSH testing - a fact which has not been emphasized in ongoing discussions regarding lowering the upper limit of normal and/or common decision limits to start treatment for hypothyroidism. In response to this need, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee for Standardization of Thyroid Function Tests worked over the years towards the goal of standardization of FT4 and TSH testing.

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Elevated levels of reactive oxygen species (ROS) have been proposed as a risk factor for the development of papillary thyroid carcinoma (PTC) in patients with Hashimoto thyroiditis (HT). However, it has yet to be proven that the total levels of ROS are sufficiently increased to contribute to carcinogenesis. We hypothesized that if the ROS levels were increased in HT, ROS-related genes would also be differently expressed in PTC with HT. To find differentially expressed genes (DEGs) we analyzed data from the Cancer Genomic Atlas, gene expression data from RNA sequencing: 33 from normal thyroid tissue, 232 from PTC without HT, and 60 from PTC with HT. We prepared 402 ROS-related genes from three gene sets by genomic database searching. We also analyzed a public microarray data to validate our results. Thirty-three ROS related genes were up-regulated in PTC with HT, whereas there were only nine genes in PTC without HT (Chi-square p-value < 0.001). Mean log₂ fold changes of up-regulated genes was 0.562 in HT group and 0.252 in PTC without HT group (t-test p-value = 0.001). In microarray data analysis, 12 of 32 ROS-related genes showed the same differential expression pattern with statistical significance. In gene ontology analysis, up-regulated ROS-related genes were related with ROS metabolism and apoptosis. Immune function-related and carcinogenesis-related gene sets were enriched only in HT group in Gene Set Enrichment Analysis. Our results suggested that ROS levels may be increased in PTC with HT. Increased levels of ROS may contribute to PTC development in patients with HT.

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Fetuin-A was considered to be involved in pathogenesis of type 2 diabetes. On the other hand, higher vascular endothelial growth factor (VEGF) expression is associated with diabetes and its vascular complications, but the mechanisms leading to higher VEGF levels are still not clear. To the best of our knowledge, there are no data to show the associations between fetuin-A and VEGF in patients with type 2 diabetes. Therefore, the aim of this study is to investigate the relationship between serum fetuin-A concentrations and serum VEGF levels in patients with type 2 diabetes. We recruited 345 patients with newly diagnosed type 2 diabetes. Serum fetuin-A concentrations and serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) method. In this study, there was a significant positive correlation between serum fetuin-A concentrations and serum VEGF levels (r=0.223, P<0.001), and the correlation remained significant even after adjustment for other confounding factors in the multivariate regression model (β=0.151, P=0.006). Mantel-Haenszel (M-H) stratified analysis showed that the degree of association of high concentrations of fetuin-A with high levels of VEGF is higher than that with low levels of VEGF (odds ratio of M-H [OR_M-H], 2.938; 95% confidence interval [CI], 1.896-4.553). In addition, this study showed that both fetuin-A and VEGF were positively associated with fasting plasma glucose (FPG), glycated hemoglobin A1c (HbA1c) and C-reactive protein (CRP). These data suggested that serum fetuin-A concentrations were positively associated with serum VEGF levels in patients with newly diagnosed type 2 diabetes.

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MicroRNA (miRNA) related genetic variation may change miRNA binding affinity and mRNA expression levels of the target genes, thus leading to altered metabolic parameters. This study explored the influence of let-7 related single nucleotide polymorphisms (SNPs) on individual susceptibility to metabolic syndrome (MetS) in a Chinese population. Seven SNPs located at the pri-let-7 gene region, pre-let-7 gene region or 3’-UTR of the KRAS gene were selected. The SNPs were genotyped in 503 MetS patients and 529 normal controls using the high-throughput Sequenom genotyping platform. Unconditional logistic regression analysis was utilized to estimate the association between these SNPs and the risk of MetS. There are three SNPs significantly associated with MetS. The A allele of rs17276588 was associated with an increased risk effect for MetS (Adjusted OR=1.75, 95%CI 1.37-2.25, P<0.001). Rs10993081 AG genotype was significantly associated with an increased risk of MetS compared with AA genotypes (Adjusted OR=1.42, 95%CI 1.11-1.83, P=0.006). Rs10877887 TC genotype was significantly associated with an increased risk of MetS compared with TT genotypes (Adjusted OR=1.52, 95% CI 1.16-1.99, P=0.002). Additionally, interactions between rs7045890 and rs712, rs17276588 and rs10877887 were significantly associated with risk of MetS. In conclusion, our study found that let-7 related genetic variation is associated with MetS and may contribute to the susceptibility of MetS. Larger, prospective studies are warranted to validate our findings.

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Early menarche is known to be associated with diabetes, however this association remains controversial. Our study aimed to investigate the possible association between age at menarche and diabetes prevalence in post-menopausal Korean women. This study included 3,254 post-menopausal Korean women aged 50-85 years from the Korea National Health and Nutrition Examination Survey IV (KNHANES 2007-2009). Logistic regression analyses were used to estimate odds ratios (ORs) for diabetes prevalence. Levels of biochemical markers were compared according to groups by age at menarche. Women in the earlier menarche age group (10-12 years) showed higher levels of fasting blood glucose (FBG) and scores of homeostatic model assessment in the insulin resistance (HOMA-IR) index than other groups (p <0.05). After adjusting for potential confounding factors, early age at menarche was significantly associated with a higher prevalence of diabetes (OR 1.86, 95% confidence intervals [CI] 1.07-3.23). The observed association remained significant despite additional adjustment for body mass index and waist circumference (OR 1.82, 95% CI 1.03-3.23) and despite further adjustments for FBG levels and HOMA-IR index (OR 2.25, 95% CI 1.11-4.55). Our findings strengthen the hypothesis that younger age at menarche is associated with increased diabetes prevalence in the Korean population.

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Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder resulting from defects in both insulin secretion and insulin activity. The deficit and dysfunction of insulin secreting β-cells are signature symptoms of T2D. Additionally, in pancreatic β-cells, a small group of genes that are abundantly expressed in most other tissues is highly selectively repressed. Monocarboxylate transporter 1 (MCT1) is one of these genes. In this study, we identified an MCT1-suppressing microRNA (hsa-miR-495) and used this microRNA together with human embryonic stem cell (hESC) derived pancreatic endoderm (PE) cells transplanted into a high-fat diet induced T2D mouse model. Glucose metabolism significantly improved and other symptoms of T2D were attenuated after the procedure. Our findings support the potential for T2D treatment using the combination of microRNA and hESC differentiated PE cells.

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Irisin is a newly identified myokine. Several studies have reported irisin concentrations in patients with gestational diabetes mellitus (GDM), but because of smaller sample sizes, the data from previous reports showed a wide range in serum/plasma irisin. Therefore, the present investigation is designed to summarize a precise confidence interval of circulating irisin in participants with GDM from a cross-sectional study in Chinese population and a meta-analysis for validation. Serum irisin was tested in patients with GDM and healthy controls (newly diagnosed cases: 61 and matched controls: 61) in the cross-sectional study. The two groups of participants were matched for age and pregnancy duration. Furthermore, we did a comprehensive meta-analysis to confirm whether serum/plasma irisin differs between participants with GDM and controls. Articles reported “circulating irisin and GDM” in Medline, PubMed, and EMBase were obtained, with the key word “myokine” or “irisin”. The comparison was analyzed by Review Manager 5.2. In the cross-sectional investigation, serum irisin showed a significant lower level in the GDM patients, compared with that in the control group. In the meta-analysis study, the summarized results of the present 5 studies in which 632 participants were included indicated that there was a lower level irisin of -58.68 ng/mL [95% confidence interval (CI)](-113.42, -3.93, P=0.04) in GDM patients than in the control group. The present cross-sectional investigation and meta-analysis is the first to show significant lower circulating irisin in subjects with GDM.

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The major purpose of this study was to investigate the effect of resveratrol (RES) on the spatial learning and memory ability in subclinical hypothyroidism (SCH) rat model and the potential mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization and the activity of hypothalamus-pituitary-thyroid (HPT) axis was detected. The spatial learning and memory ability was tested using Morris water maze (MWM) and Y-maze. The protein expressions of synaptotagmin-1 (syt-1) and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured via western blot. The results showed that SCH rat model was successfully duplicated. The SCH rats showed impaired learning and memory in the behavioral tests. However, these changes were reversed by the treatment of RES (15mg/kg) and levothyroxine (LT4). Moreover, RES treated rats exhibited reduced plasma TSH level and hypothalamic thyrotropin releasing hormone (TRH) mRNA expression, which suggested that the imbalance of HPT axis in the SCH rats could be reversed by RES treatment. Furthermore, RES treatment up-regulated the protein levels of syt-1 and BDNF in hippocampus. These findings indicated an amelioration effect of RES on the spatial learning and memory in the SCH rats, the mechanism of which might be involved with its ability of modifying the hyperactive HPT axis and up-regulating the hippocampal hypo-expression of syt-1 and BDNF.

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Guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), are primarily present in the intestine and maintain homeostasis in body fluids. Recently, rats whose macrophages overexpress Gn and GC-C were found to be resistant to diet-induced obesity. Considering that obesity is strongly related to a chronic inflammatory state in white adipose tissues, it is possible that Gn-GC-C macrophages contribute to the regulation of inflammation. In the present study, we investigated the inflammatory state of mesenteric fat in rats transgenic for both Gn and GC-C (double-transgenic [dTg] rats) by evaluating the levels of cyclic guanosine monophosphate (cGMP), a second messenger of Gn-GC-C, cGMP-dependent protein kinase (PKG), and phosphorylated vasodilator-stimulated phosphoprotein (VASP), a target protein of PKG. The levels of cGMP in dTg rats was higher than in WT rats fed the same diet. Although there were no significant differences in levels of PKG and phosphorylated VASP between WT and dTg rats fed a standard diet (STD), these levels in dTg rats fed a high fat diet (HFD) were markedly increased compared with levels in HFD WT rats. Furthermore, mRNA levels of proinflammatory factors in mesenteric fat were lower in HFD dTg rats than in HFD WT rats and were similar to levels in STD WT and dTg rats. These results indicate that the Gn-GC-C system in macrophages regulates the cGMP-PKG-VASP pathway and controls obesity through the downregulation of proinflammatory factors.

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Human chorionic gonadotropin (hCG) has weak thyroid-stimulating activity because of its homology with thyroid stimulating hormone (TSH). In twin-twin transfusion syndrome (TTTS), which is a severe complication of monochorionic twin pregnancies, a close association between maternal serum hCG concentration and TTTS has been reported. And, TTTS can be treated by fetoscopic laser coagulation of the communicating vessels. To clarify the relationship between maternal serum hCG and maternal thyroid function in TTTS, the present study investigated the change in thyroid hormone and hCG levels after laser therapy. The protocol included collection of serial maternal blood samples in TTTS before laser therapy, and at two and four weeks after laser therapy. For 131 cases of TTTS, the following parameters were determined at each point: hCG, TSH, free triiodothyronine (fT3), and free thyroxine (fT4). The multiple of the median (MoM) of pre-operative hCG concentration in TTTS was 5.39 MoM (interquartile range, 2.83 - 8.64). There was a moderate positive correlation between hCG and fT3 in TTTS pre-operatively (R = 0.22, P = 0.030). fT4 was also positively correlated with hCG (R = 0.33, P < 0.001). Some cases showed very high concentration in fT3. When laser therapy for TTTS was effective, the hCG concentration significantly decreased, and fT3 and fT4 decreased progressively in concert with the decrease in hCG. The relationship between hCG and thyroid function in TTTS supports the finding of TTTS as a novel etiology of hCG-mediated hyperthyroidism during pregnancy.

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